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DURAGESIC® (fentanyl transdermal) patches are intended for transdermal use (on intact skin) only. Do not use a DURAGESIC® (fentanyl transdermal) patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way.

The safety of DURAGESIC® (fentanyl transdermal system) has not been established in children under 2 years of age. DURAGESIC® (fentanyl transdermal) should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS – Pediatric Use).

DURAGESIC® (fentanyl transdermal) is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid tolerant patients may lead to fatal respiratory depression. Overestimating the DURAGESIC® (fentanyl transdermal) dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean half-life is approximately 20-27 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after DURAGESIC® removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 20-27 hours after system removal.

DURAGESIC® (fentanyl transdermal) should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists.

All patients and their caregivers should be advised to avoid exposing the DURAGESIC® (fentanyl transdermal) application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. A clinical pharmacology trial conducted in healthy adult subjects has shown that the application of heat over the DURAGESIC® system increased mean fentanyl AUC values by 120% and mean Cmax values by 61%.

Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing DURAGESIC® (fentanyl transdermal) systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the DURAGESIC® (fentanyl transdermal) dose should be adjusted if necessary.

Death and other serious medical problems have occurred when people were accidentally exposed to DURAGESIC® (fentanyl transdermal) . Examples of accidental exposure include transfer of a DURAGESIC® (fentanyl transdermal) patch from an adult's body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver's skin to the medication in the patch while the caregiver was applying or removing the patch.

Placing DURAGESIC® (fentanyl transdermal) in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death.

Misuse, Abuse and Diversion of Opioids

Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing DURAGESIC® (fentanyl transdermal) in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

DURAGESIC® (fentanyl transdermal) has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death (see WARNINGS and Drug Abuse And Addiction).

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Hypoventilation (Respiratory Depression)

Serious or life-threatening hypoventilation may occur at any time during the use of DURAGESIC® (fentanyl transdermal) especially during the initial 24-72 hours following initiation of therapy and following increases in dose.

Because significant amounts of fentanyl continue to be absorbed from the skin for 20-27 hours or more after the patch is removed, hypoventilation may persist beyond the removal of DURAGESIC® (fentanyl transdermal) . Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized.

The use of concomitant CNS active drugs requires special patient care and observation.

Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in DURAGESIC® (fentanyl transdermal) . Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration.

Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous.

DURAGESIC® (fentanyl transdermal) should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression. In such patients, even usual therapeutic doses of DURAGESIC® (fentanyl transdermal) may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose.

Chronic Pulmonary Disease

Because potent opioids can cause serious or life-threatening hypoventilation, DURAGESIC® (fentanyl transdermal) should be administered with caution to patients with pre-existing medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure.

Head Injuries and Increased Intracranial Pressure

DURAGESIC® (fentanyl transdermal) should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. DURAGESIC® (fentanyl transdermal) should be used with caution in patients with brain tumors.

Interactions with Other CNS Depressants

The concomitant use of DURAGESIC® (fentanyl transdermal system) with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced.

Interactions with Alcohol and Drugs of Abuse

Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.

Interactions with CYP3A4 Inhibitors

The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving DURAGESIC® (fentanyl transdermal) and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY – Drug Interactions, PRECAUTIONS, and DOSAGE AND ADMINISTRATION for further information).

General

DURAGESIC® (fentanyl transdermal system) should not be used to initiate opioid therapy in patients who are not opioid-tolerant. Children converting to DURAGESIC® (fentanyl transdermal) should be opioid-tolerant and 2 years of age or older (see BOX WARNING).

Patients, family members, and caregivers should be instructed to keep patches (new and used) out of the reach of children and others for whom DURAGESIC® was not prescribed. A considerable amount of active fentanyl remains in DURAGESIC® (fentanyl transdermal) even after use as directed. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death.

Cardiac Disease

Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias.

Hepatic or Renal Disease

Insufficient information exists to make recommendations regarding the use of DURAGESIC® (fentanyl transdermal) in patients with impaired renal or hepatic function. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl.

Use in Pancreatic/Biliary Tract Disease

DURAGESIC® (fentanyl transdermal) may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like DURAGESIC® (fentanyl transdermal) may cause increases in the serum amylase concentration.

Tolerance

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical Dependence

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood concentration of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION – Discontinuation of DURAGESIC® (fentanyl transdermal) ).

Ambulatory Patients

Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given DURAGESIC® (fentanyl transdermal) should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.

Information for Patients

Patients and their caregivers should be provided with a Medication Guide each time

DURAGESIC® (fentanyl transdermal) is dispensed because new information may be available.

Patients receiving DURAGESIC® (fentanyl transdermal) patches should be given the following instructions by the physician:

1. Patients should be advised that DURAGESIC® patches contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.
2. Patients should be advised that each DURAGESIC® (fentanyl transdermal) patch may be worn continuously for 72 hours, and that each patch should be applied to a different skin site after removal of the previous transdermal patch.
3. Patients should be advised that DURAGESIC® (fentanyl transdermal) patches should be applied to intact, non-irritated, and non-irradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should be advised of the following:
   • In young children or persons with cognitive impairment, the patch should be put on the upper back to lower the chances that the patch will be removed and placed in the mouth.
   • Hair at the application site should be clipped (not shaved) prior to patch application.
   • If the site of DURAGESIC® (fentanyl transdermal) application must be cleansed prior to application of the patch, do so with clear water.
   • Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics.
   • Allow the skin to dry completely prior to patch application.
4. Patients should be advised that DURAGESIC® (fentanyl transdermal) should be applied immediately upon removal from the sealed pouch and after removal of the protective liner. Additionally the patient should be advised of the following:
   • The DURAGESIC® (fentanyl transdermal) patch should not be used if the pouch seal is broken, or if the patch is cut, damaged, or changed in any way.
   • The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges.
   • The patch should not be folded so that only part of the patch is exposed.
5. Patients should be advised that the dose of DURAGESIC® (fentanyl transdermal) or the number of patches applied to the skin should NEVER be adjusted without the prescribing healthcare professional's instruction.
6. Patients should be advised that while wearing the patch, they should avoid exposing the DURAGESIC® (fentanyl transdermal) application site and surrounding area to direct external heat sources, such as:
   • heating pads,
   • electric blankets,
   • sunbathing,
   • heat or tanning lamps,
   • saunas,
   • hot tubs or hot baths, and
   • heated water beds, etc.
7. Patients should also be advised of a potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body temperature due to strenuous exertion while wearing the patch should contact their physician.
8. Patients should be advised that if they experience problems with adhesion of the DURAGESIC® (fentanyl transdermal) patch, they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients may overlay the patch with a transparent adhesive film dressing (e.g., BioclusiveTM or TegadermTM).
9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a different skin site.
10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down the toilet used DURAGESIC® (fentanyl transdermal) patches after removal from the skin.
11. Patients should be advised that DURAGESIC® (fentanyl transdermal) may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).
12. Patients should be advised to refrain from any potentially dangerous activity when starting on DURAGESIC® (fentanyl transdermal) or when their dose is being adjusted, until it is established that they have not been adversely affected.
13. Patients should be advised that DURAGESIC® (fentanyl transdermal) should not be combined with alcohol or other CNS depressants (e.g. sleep medications, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death.
14. Patients should be advised to consult their physician or pharmacist if other medications are being or will be used with DURAGESIC® (fentanyl transdermal) .
15. Patients should be advised of the potential for severe constipation.
16. Patients should be advised that if they have been receiving treatment with DURAGESIC® (fentanyl transdermal) and cessation of therapy is indicated, it may be appropriate to taper the DURAGESIC® (fentanyl transdermal) dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.
17. Patients should be advised that DURAGESIC® contains fentanyl, a drug with high potential for abuse.
18. Patients, family members, and caregivers should be advised to protect DURAGESIC® (fentanyl transdermal) from theft or misuse in the work or home environment.
19. Patients should be instructed to keep DURAGESIC® (fentanyl transdermal) in a secure place out of the reach of children due to the high risk of fatal respiratory depression.
20. Patients should be advised that DURAGESIC® (fentanyl transdermal) should never be given to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended.
21. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person, they should immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual.
22. When DURAGESIC® (fentanyl transdermal) is no longer needed, the unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.
23. Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult a physician prior to initiating or continuing therapy with DURAGESIC® (fentanyl transdermal) .
24. Patients should be informed that accidental exposure or misuse may lead to death or other serious medical problems.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In a two-year carcinogenicity study conducted in rats, fentanyl was not associated with an increased incidence of tumors at subcutaneous doses up to 33 μg/kg/day in males or 100 μg/kg/day in females (0.16 and 0.39 times the human daily exposure obtained via the 100 mcg/h patch based on AUC0-24h comparison). There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in-vitro assays.

The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.

Pregnancy – Pregnancy Category C

No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported.

The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 μg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.

Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis).

There are no adequate and well-controlled studies in pregnant women. DURAGESIC® (fentanyl transdermal) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.

The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m² basis.

Labor and Delivery

Fentanyl readily passes across the placenta to the fetus; therefore, DURAGESIC® (fentanyl transdermal) is not recommended for analgesia during labor and delivery.

Nursing Mothers

Fentanyl is excreted in human milk; therefore, DURAGESIC® (fentanyl transdermal) is not recommended for use in nursing women because of the possibility of effects in their infants.

Pediatric Use

The safety of DURAGESIC® (fentanyl transdermal) was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/h and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of DURAGESIC® (fentanyl transdermal) therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. Approximately 90% of the total daily opioid requirement (DURAGESIC® (fentanyl transdermal) plus rescue medication) was provided by DURAGESIC® (fentanyl transdermal) .

DURAGESIC® (fentanyl transdermal) was not studied in children under 2 years of age.

DURAGESIC® (fentanyl transdermal) should be administered to children only if they are opioid-tolerant and 2 years of age or older (see DOSAGE AND ADMINISTRATION and BOX WARNING).

To guard against accidental ingestion by children, use caution when choosing the application site for DURAGESIC® (see DOSAGE AND ADMINISTRATION) and monitor adhesion of the system closely.

Geriatric Use

Data from intravenous studies with fentanyl suggest that the elderly patients may have reduced clearance and a prolonged half-life. Moreover elderly patients may be more sensitive to the active substance than younger patients. A study conducted with the DURAGESIC® fentanyl transdermal patch in elderly patients demonstrated that fentanyl pharmacokinetics did not differ significantly from young adult subjects, although peak serum concentrations tended to be lower and mean half-life values were prolonged to approximately 34 hours.

Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in non-tolerant patients or when opioids are given in conjunction with other agents that depress respiration.

DURAGESIC® (fentanyl transdermal) should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND ADMINISTRATION).

Last reviewed on RxList: 10/7/2010
This monograph has been modified to include the generic and brand name in many instances.